TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients

Pernille Bræmer Hertel; Dongsheng Tu; Bent Laursen Ejlertsen; Maj-Britt Raaby Jensen; Eva Balslev; Shan Jiang; Frances P. O'Malley; Kathleen I. Pritchard; Lois E. Shepherd; Annette Bartels; Nils Brunner; Torsten O. Nielsen

doi:10.1007/s10549-011-1896-1

TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients

Pernille Bræmer Hertel, Dongsheng Tu, Bent Laursen Ejlertsen, Maj-Britt Raaby Jensen, Eva Balslev, Shan Jiang, Frances P. O'Malley, Kathleen I. Pritchard, Lois E. Shepherd, Annette Bartels, Nils Brunner, Torsten O. Nielsen

Institut for Klinisk Medicin

11 Citationer (Scopus)

Abstract

HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42-0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.

Originalsprog	Engelsk
Tidsskrift	Breast Cancer Research and Treatment
Vol/bind	132
Udgave nummer	1
Sider (fra-til)	225-234
Antal sider	10
ISSN	0167-6806
DOI	https://doi.org/10.1007/s10549-011-1896-1
Status	Udgivet - feb. 2012

Emneord

Det tidligere LIFE
TIMP-1
HER2
TOP2A
Prediction
Breast cancer
NCIC CTG MA.5

FN’s Verdensmål

Dette resultat bidrager til følgende verdensmål

Adgang til dokumentet

10.1007/s10549-011-1896-1

Citationsformater

Hertel, P. B., Tu, D., Ejlertsen, B. L., Jensen, M-B. R., Balslev, E., Jiang, S., O'Malley, F. P., Pritchard, K. I., Shepherd, L. E., Bartels, A., Brunner, N., & Nielsen, T. O. (2012). TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients. Breast Cancer Research and Treatment, 132(1), 225-234. https://doi.org/10.1007/s10549-011-1896-1

TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients. / Hertel, Pernille Bræmer; Tu, Dongsheng; Ejlertsen, Bent Laursen et al.

I: Breast Cancer Research and Treatment, Bind 132, Nr. 1, 02.2012, s. 225-234.

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Hertel, PB, Tu, D, Ejlertsen, BL, Jensen, M-BR, Balslev, E, Jiang, S, O'Malley, FP, Pritchard, KI, Shepherd, LE, Bartels, A , Brunner, N & Nielsen, TO 2012, 'TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients', Breast Cancer Research and Treatment, bind 132, nr. 1, s. 225-234. https://doi.org/10.1007/s10549-011-1896-1

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title = "TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients",

abstract = "HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42-0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.",

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author = "Hertel, {Pernille Br{\ae}mer} and Dongsheng Tu and Ejlertsen, {Bent Laursen} and Jensen, {Maj-Britt Raaby} and Eva Balslev and Shan Jiang and O'Malley, {Frances P.} and Pritchard, {Kathleen I.} and Shepherd, {Lois E.} and Annette Bartels and Nils Brunner and Nielsen, {Torsten O.}",

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doi = "10.1007/s10549-011-1896-1",

language = "English",

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T1 - TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients

AU - Hertel, Pernille Bræmer

AU - Tu, Dongsheng

AU - Ejlertsen, Bent Laursen

AU - Jensen, Maj-Britt Raaby

AU - Balslev, Eva

AU - Jiang, Shan

AU - O'Malley, Frances P.

AU - Pritchard, Kathleen I.

AU - Shepherd, Lois E.

AU - Bartels, Annette

AU - Brunner, Nils

AU - Nielsen, Torsten O.

PY - 2012/2

Y1 - 2012/2

N2 - HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42-0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.

AB - HER2 amplification, TOP2A aberrations, and absence of tissue inhibitor of metalloproteinase (TIMP-1) expression in breast carcinomas have been shown to be associated with incremental benefit from anthracycline-containing adjuvant chemotherapy, and this study was undertaken to validate these findings in a similar, but independent, randomized clinical trial. TIMP-1 was examined by immunohistochemistry in archival tumor tissue from 403 of 716 premenopausal high-risk patients with known HER2 and TOP2A status who were randomized to cyclophosphamide, epirubicin, and fluorouracil (CEF) or cyclophosphamide, methotrexate, and fluorouracil (CMF) in the MA.5 trial. Ninety-eight (24%) patients had no TIMP-1 staining of tumor cells, 27% were HER2 amplified, and 18% were TOP2A aberrant. Forty-four percentage was classified as HT responsive (HER2 amplified and/or TIMP-1 negative) and 37% as 2T responsive (TOP2A aberrant and/or TIMP-1 negative). There was no heterogeneity in treatment effect of CEF versus CMF according to TIMP-1. In HT-responsive patients, CEF was superior to CMF with an improved RFS (adjusted HR, 0.64; 95% CI, 0.42-0.97), but this was not significant for OS (adjusted HR, 0.66; 95% CI, 0.42-1.04). A significant HT profile versus treatment interaction was detected for OS (P = 0.03). In 2T-responsive patients, CEF seemed to improve RFS compared to CMF (adjusted HR, 0.67; 95% CI, 0.43-1.03) and improved OS (adjusted HR, 0.58; 95% CI, 0.36-0.93). A significant 2T profile versus treatment interaction was detected for OS (P = 0.01). With this study, we validate a more substantial reduction in mortality by CEF compared to CMF in patients with an HT- or 2T-responsive profile; however, we could not show a similarly significant reduction in RFS events, where a benefit of CEF over CMF was found irrespective of TIMP-1 status. Further studies are necessary before the HT and 2T profiles may be used to direct the use of anthracyclines.

KW - Former LIFE faculty

KW - TIMP-1

KW - HER2

KW - TOP2A

KW - Prediction

KW - Breast cancer

KW - NCIC CTG MA.5

U2 - 10.1007/s10549-011-1896-1

DO - 10.1007/s10549-011-1896-1

M3 - Journal article

C2 - 22160637

SN - 0167-6806

VL - 132

SP - 225

EP - 234

JO - Breast Cancer Research and Treatment

JF - Breast Cancer Research and Treatment

IS - 1

ER -

TIMP-1 in combination with HER2 and TOP2A for prediction of benefit from adjuvant anthracyclines in high-risk breast cancer patients

Abstract

Emneord

FN’s Verdensmål

Adgang til dokumentet

Fingeraftryk

Citationsformater